The objectives of the current study are: 1) to analyze critically at both the LM and EM levels the structure, origin, and nature of the corneal innervation and 2) to determine the brainstem projections and synaptic connections of corneal afferent neurons. In the first series of experiments, horseradish peroxidase (HRP) will be injected into either the trigeminal, superior cervical, or ciliary ganglion of rats and monkeys. The enzyme will be taken up by the neuronal cell bodies and transported anterogradely to the peripheral nerve endings in the cornea. Each population of labeled neural elements will then be analyzed critically to determine its origin, distribution, ultrastructure, and mode of termination within the cornea. In addition, detailed electron microscopic studies of human corneal innervation will be performed on corneas obtained from fresh autopsy material and from patients whose corneas have been excised for corneal transplant. In a second set of experiments, the significance of the vesicles found in many corneal nerve terminals will be investigated. Experiments will be performed in animal models to determine if the vesicles (containing most likely trophic or neurotransmitter substances) can be released from the corneal nerve terminals by antidromic stimulation of the ophthalmic nerve or mechanical stimulation of the corneal surface. Substance P (SP)-containing fibers in human and animal corneas will be examined critically at both the LM and EM level with respect to their structure, distribution, and mode of termination. In animal models, it will be determined if these fibers release SP from their terminals following antidromic stimulation of the ophthalmic nerve or mechanical stimulation of the corneal surface. Finally, the brainstem sites of termination of corneal afferent neurons will be determined experimentally at the LM and EM levels by the method of transganglionic transport of HRP. The distribution, ultrastructure, and synaptic relationships of the fibers will be analyzed to determine the CNS substrates subserving corneal sensation and corneal reflexes. The results of the present study should increase significantly our understanding of the anatomy of the corneal innervation, the role of the corneal innervation in corneal physiology, and the peripheral and central neural mechanisms of corneal sensation.